16-74713799-G-A

Variant names:

• chr16-74713799-G-A
• rs563533561
• ENST00000562145.1:n.1231C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_024306.5(FA2H):​c.*391C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 220,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: FA2H NM_024306.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.17
• Publications: 0 publications found

Genes affected

FA2H (HGNC:21197): (fatty acid 2-hydroxylase) This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]

FA2H Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 35

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000696 (106/152352) while in subpopulation NFE AF = 0.00101 (69/68038). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FA2H	NM_024306.5	c.*391C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000219368.8	NP_077282.3
FA2H	XM_011523319.3	c.*391C>T		3_prime_UTR_variant	Exon 7 of 7		XP_011521621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FA2H	ENST00000562145.1	n.1231C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
FA2H	ENST00000219368.8	c.*391C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_024306.5	ENSP00000219368.3
FA2H	ENST00000567683.5	n.*789C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000455126.1
FA2H	ENST00000567683.5	n.*789C>T		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000455126.1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000452 AC: 31 AN: 68622 Hom.: 0 Cov.: 0 AF XY: 0.000480 AC XY: 17 AN XY: 35416

African (AFR) AF: 0.00 AC: 0 AN: 3236

American (AMR) AF: 0.000626 AC: 3 AN: 4792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1746

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.000164 AC: 1 AN: 6088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000655 AC: 27 AN: 41244

Other (OTH) AF: 0.00 AC: 0 AN: 3826

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74490

African (AFR) AF: 0.000409 AC: 17 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.000650

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 35 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.030
DANN	Benign	0.39
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs563533561; hg19: chr16-74747697;